Abstract / Summary Glioblastoma multiforme (GBM) is an aggressive brain tumor that generally recurs locally and has a median survival <18 months. Treatment typically involves surgery followed by radiation and chemotherapy but the challenge remains to provide sufficient radiation dose to sterilize tumor bed without unacceptable toxicity in surrounding normal brain. A randomized clinical trial studying brachytherapy radiation boost to tumor bed with and without sequentially applied local heat showed a doubling of two-year survival in GBM compared to brachytherapy alone. Although that 31% two-year survival rate is higher than current state of the art treatment approaches for GBM, previous thermobrachytherapy studies used University prototype heating systems that were never commercialized, and thus the approach was discontinued. With alternative treatments still failing to match prior results, the time has come to optimize thermobrachytherapy. Ensuing in vivo studies have shown that synergy between heat (HT) and radiation (RT) is maximized when the two therapies are applied simultaneously. To meet the urgent need for improved survival following brain tumor surgery, we propose a dual-modality thermobrachytherapy (TBT) balloon implant to fill the resection cavity and further increase the survival benefit seen in prior studies by: i) delivering HT and RT more uniformly to tumor bed; ii) providing potent thermal enhancement of RT response up to 5X in tumor bed by combining HT and RT simultaneously; iii) beginning RT of tumor bed immediately after surgery before tumor cell migration; and iv) improving patient satisfaction and reducing cost by decreasing treatment time from 3-6 weeks of daily external beam RT to <5 days total therapy. Our premise is that by applying local heat and brachytherapy simultaneously for maximum synergy and uniformly to the resection cavity wall for effective localization of effect before tumor cells migrate, we can significantly enhance local response and survival while minimizing peripheral toxicity and thereby improve clinical outcomes. Our Phase I development has three specific aims: i) to fabricate a dual-therapy balloon device; ii) to evaluate the device for compatibility of HT and RT components and characterize thermal and radiation dosimetry in laboratory studies; and iii) demonstrate appropriate heat distributions that coincide with computer treatment plans in in vivo animal perfused tissue studies. After demonstrating safety and effectiveness in followup clinical trials in Phase II, we anticipate neurosurgeons and oncologists associated with ~250 brain surgery centers already owning HDR afterloaders will embrace this new technology due to obvious need for improved therapy in >52,000 resected brain tumors annually in the US, impressive clinical precedent in GBM with inferior thermobrachytherapy approaches, and established regulatory pathway for component technologies. While this development is focused towards brain tumor therapy, the TBT balloon procedure is expected to find application in other tumor resection sites including head and neck, breast, lung, and sarcoma (with potentially ~600,000 patients annually in US) following successful launch in brain tumors.